EGFR is a receptor-type tyrosine kinase, exerts its physiological function in normal tissue when being bound to Epidermal Growth Factor (EGF), which is a ligand, and contributes to growth, apoptosis inhibition, etc., in epithelial tissues (Non-Patent Document (NPD) 1).
In addition, EGFR is one of the oncogenes, and amplification of the EGFR gene and high expression or mutation of its protein are seen in various cancer types such as head and neck cancer, breast cancer, colorectal cancer, esophagus cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, and brain tumor (Non-Patent Document (NPD) 2). In Japan and western countries, approximately 170 to 375 in every 100,000 people perish due to cancer every year, and cancer ranks high as a cause of death (Non-Patent Document (NPD) 3). Among these, the death toll due to lung cancer reaches approximately 1,400,000 per year worldwide, and since non-small cell lung cancer accounts for 80% or more of lung cancers, there has been a desire for the development of an effective therapy for the same (Non-patent Document (NPD) 4).
In recent years, responsible genes for these cancers are being identified, and a mutation in the EGFR gene is also one of them and results in an active mutated EGFR protein. An active mutated EGFR protein is, for example, a deletion of amino acid at positions 746-750 (EGFR (d746-750)), a mutation of amino acid at position 858 from leucine to arginine (EGFR (L858R)), or the like. Such mutations are reported, for example, in 20-40% of non-small cell lung cancer cases in Japan, and in 10-15% of non-small cell lung cancer cases in western countries. Since non-small cell lung cancer having these mutations is highly susceptible against gefitinib (product name: Iressa (Registered trademark)) and erlotinib (product name: Tarceva (Registered trademark)) which are chemical agents (EGFR inhibitors) that inhibit the kinase activity of EGFR, these chemical agents are used as therapeutic agents in Japan and western countries. However, the cancer acquires resistance against gefitinib and erlotinib after 6 to 12 months from the beginning of use and therapeutic effect becomes weak. Therefore, this acquired resistance has been a serious problem for treating non-small cell lung cancer having a highly-susceptible mutated EGFR. It has been revealed that approximately 50% of the acquired resistance is due to emergence of a resistant mutated EGFR protein (EGFR (d746-750/T790M) or EGFR (T790M/L858R)) having a second mutation in the EGFR gene resulting in amino acid at position 790 to change from threonine to methionine. It has been an important task to develop a therapeutic agent that is effective against non-small cell lung cancer having this drug resistant mutated EGFR (Non-patent Document (NPD) 5).
On the other hand, skin abnormality and alimentary canal disorder are reported as common side effects of the EGFR inhibitors of gefitinib and erlotinib, which are clinically used as therapeutic agents at present, and of EGFR inhibitors such as BIBW2992 etc., which are under clinical trial. It is widely thought that these side effects are caused by the EGFR inhibitors inhibiting the activity of not only a mutated EGFR expressed in non-small cell lung cancer, but also the activity of the wild-type EGFR (EGFR (WT)) expressed in the skin or alimentary canal (Non-Patent Document (NPD) 1). From a standpoint of side effect reduction, it is considered to be preferable to have a weak inhibitory activity against EGFR (WT) in normal tissues.
Thus, there is expectation of possibly suppressing growth of non-small cell lung cancer cells having a drug resistant mutated EGFR through administration of a chemical agent having weaker inhibitory activity against the wild-type EGFR when compared to inhibitory activity against the drug resistant mutated EGFR whose amino acid at position 790 has mutated to methionine, at an administration dose where the side effect to the skin or alimentary canal does not appear strongly. This is predicted to contribute to treating the cancer, and prolonging life and improving QOL of patients. In addition, if the chemical agent has weak inhibitory activity against the wild-type EGFR but has strong in inhibitory activity not only against drug resistant mutated EGFR but also against highly-susceptible mutated EGFRs such as the EGFR (d746-750) and the EGFR (L858R) etc., which are highly susceptible against gefitinib and erlotinib; there is expectation of possibly suppressing growth of non-small cell lung cancer cells expressing a highly-susceptible mutated EGFR or a drug resistant mutated EGFR at an administration dose where the side effect to the skin or alimentary canal does not appear strongly, or expectation of possibly reducing the frequency of drug resistant mutated EGFR that emerges, as acquired resistance, from non-small cell lung cancer expressing a highly-susceptible mutated EGFR. This is predicted to contribute to treating the cancer, and prolonging life and improving QOL of patients. Furthermore, since expressions of highly-susceptible mutated EGFR and drug resistant mutated EGFR can be used in the actual scene of therapy as indices for stratification to enable selection of patients, they contribute greatly from an ethical viewpoint.
As a compound having a structure analogous to a compound according to present invention, N-(3-(4-amino-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-5-yl)phenyl)benzamide derivative is known (Patent Document (PTD) 1). Although Patent Document 1 describes using the amide compound for treating diseases characterized by B-RAF kinase, the document does not disclose specific tests and results therefrom corroborating a kinase inhibiting activity, and such activity is not confirmed.